Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1–derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.

肺气肿是一种进行性和致命的肺部疾病，无法治愈，其特征是肺泡变薄、扩大和破坏，导致气体交换受损。疾病进展部分归因于肺中 VEGF（血管内皮生长因子）信号传导的失调和肺细胞凋亡增加。在这里，我们询问 PR1P（Prominin-1 衍生肽），一种我们设计的增加 VEGF 与内皮细胞结合的新型短肽，是否可用于改善体外和体内肺气肿模型的结果。我们使用计算机模拟和体外和体内研究表明，PR1P 通过结合 VEGF 并阻止其蛋白水解降解上调内源性 VEGF 受体 2 信号传导。通过这样做，PR1P 减轻了毒素诱导的肺细胞凋亡，包括体外的香烟烟雾提取物和小鼠体内的LPS 。值得注意的是，吸入 PR1P 在 30 分钟内导致鼠肺中 VEGF 浓度显着增加，24 小时后仍比对照动物高出两倍以上。最后，吸入 PR1P 可减少 4 天和 21 天弹性蛋白酶诱导的小鼠肺气肿模型中的急性肺损伤。总之，这些结果突出了 PR1P 作为治疗肺气肿或其他以 VEGF 信号失调为特征的肺部疾病的新型治疗剂的潜力。